Regulation of immune checkpoints: from molecular mechanisms to clinical therapies

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by targeting crucial coinhibitory pathways. Pathways involving PD-1/PD-L1 and CTLA-4 are essential for immune homeostasis but are frequently exploited by tumors to evade immune surveillance. ICIs block these interactions, unleashing a potent antitumor immune response. However, broad clinical efficacy is limited by low response rates, immune-related adverse events, and the pervasive challenge of primary or acquired resistance. This review summarizes the fundamental molecular mechanisms of key checkpoints (PD-1/PD-L1, CTLA-4, TIM-3) and highlights recent clinical progress in ICI monotherapies and combination strategies. We systematically explore multifaceted mechanisms of resistance, encompassing both tumor-intrinsic and extrinsic factors. Furthermore, we outline novel therapeutic approaches being designed to overcome this resistance. Finally, we discuss promising predictive biomarkers and precision immuno-oncology strategies. This review provides a critical framework for navigating the current landscape and offers a rationale to guide the future development of effective combination therapies to improve patient outcomes.